Urinary neutrophil gelatinase-associated lipocalin rules out nephrotoxic acute kidney injury in children.

BACKGROUND: Nephrotoxic medication exposure is a common cause of acute kidney injury (AKI) in hospitalized children. A key component of the NINJA quality improvement initiative is systematic daily serum creatinine assessment in non-critically ill children exposed to ≥ 3 nephrotoxic medications on 1 day, or intravenous aminoglycoside or vancomycin for ≥ 3 days. Daily venipuncture is invasive and associated with disposable and personnel healthcare costs. Urine neutrophil gelatinase-associated lipocalin (uNGAL) is a marker of renal tubular injury associated with certain nephrotoxic medications. We investigated whether uNGAL is a reliable screening tool for AKI in NINJA and could decrease the need for daily venipuncture. METHODS: This two-center prospective study enrolled 113 children who met NINJA criteria from May 2018 through March 2019. Daily urine samples were obtained for up to the first 7 days of qualifying exposure and 2 days after exposure ended. Our primary outcome was severe AKI (KDIGO stage 2 or 3 AKI). Maximum uNGAL was highest concentration on the day of, or 3 days prior to, severe AKI. The highest uNGAL level from all assessment days was used for patients who did not develop AKI or severe AKI. RESULTS: Urine NGAL thresholds of 150 and 300 ng/ml demonstrated excellent specificity (92.4 and 97.1% respectively) and negative predictive values (93.3 and 92.8% respectively) for ruling out severe AKI. CONCLUSIONS: We suggest that uNGAL could be used to supplant some of the daily serum creatinine venipunctures in NINJA. The most optimal combination of serum creatinine and uNGAL assessment requires further study.

Composite Health Outcomes in Pediatric and Young Adult Kidney Transplant Recipients.

OBJECTIVE: To assess composite health outcomes in pediatric and young adult kidney transplant recipients following kidney transplantation. STUDY DESIGN: We conducted a cross-sectional study of all recipients at our center who had a 1-, 3-, 5-, and/or 10-year transplant anniversary visit between October 2008 and February 2015. The kidney transplant recipients were assessed at each time point according to an outcome measure consisting of 15 pass/fail criteria in 5 domains: allograft health, rejection and immunology, infection, cardiovascular health, and growth. RESULTS: We analyzed 148 patients at 231 transplantation anniversary visit time points; 52 of 82 (63%) patients assessed at 1 year had an ideal outcome, meeting at least 13 of the 15 criteria. This decreased to 37% at year 3, 40% at year 5, and 26% at year 10 (P < .01). The most common failures across all time points occurred in the domains of growth (43%-52% passing) and cardiovascular health (33%-51% passing). Allograft health declined significantly, decreasing from 74% at year 1 to 33% at year 10 (P < .01). The percentage of patients with graft failure increased from 2.4% at 1 year to 39.5% at 10 years (P < .01), and patient deaths increased from 0 to 11% (P < .01) in the same time frame. CONCLUSIONS: Ideal outcomes for pediatric kidney transplant recipients decrease over time with growth, cardiovascular health, and allograft health as the primary failure modes. Understanding the composite health of young recipients will allow primary care providers and nephrologists alike to evaluate the overall health of kidney transplant recipients and focus clinical care on the most common sequelae.

Mycophenolate mofetil-related leukopenia in children and young adults following kidney transplantation: Influence of genes and drugs.

MMF is commonly prescribed following kidney transplantation, yet its use is complicated by leukopenia. Understanding the genetics mediating this risk will help clinicians administer MMF safely. We evaluated 284 patients under 21 years of age for incidence and time course of MMF-related leukopenia and performed a candidate gene association study comparing the frequency of 26 SNPs between cases with MMF-related leukopenia and controls. We matched cases by induction, steroid duration, race, center, and age. We also evaluated the impact of induction and SNPs on time to leukopenia in all cases. Sixty-eight (24%) patients had MMF-related leukopenia, of which 59 consented for genotyping and 38 were matched with controls. Among matched pairs, no SNPs were associated with leukopenia. With non-depleting induction, UGT2B7-900A>G (rs7438135) was associated with increased risk of MMF-related leukopenia (P = .038). Time to leukopenia did not differ between patients by induction agent, but 2 SNPs (rs2228075, rs2278294) in IMPDH1 were associated with increased time to leukopenia. MMF-related leukopenia is common after transplantation. UGT2B7 may influence leukopenia risk especially in patients without lymphocyte-depleting induction. IMPDH1 may influence time course of leukopenia after transplant.

Integration of the Renal Angina Index and Urine Neutrophil Gelatinase-Associated Lipocalin Improves Severe Acute Kidney Injury Prediction in Critically Ill Children and Young Adults.

Introduction: Acute kidney injury (AKI) occurs in one-fourth of children and young adults admitted to pediatric intensive care unit (PICU). Severe AKI (sAKI; Kidney Disease: Improving Global Outcomes stage 2 or 3) is associated with morbidity and mortality. An AKI risk stratification system, the Renal Angina Index (RAI) calculated at 12 hours of admission, exhibits excellent performance to rule out sAKI at 72 hours of admission. We found that integration of urine neutrophil gelatinase-associated lipocalin (NGAL) with RAI improves prediction of sAKI. We now report the first-year results after implementation of our prospective automated RAI-NGAL clinical decision support (CDS) program. Methods: Patients 3 months to 25 years of age were eligible. Admission order sets have a conditional order for urine NGAL released when a 12-hour RAI ≥8. The primary outcome was sAKI any time at days 2 to 4 of admission. We assessed performance of the RAI and RAI+/NGAL to predict the primary outcome. Results: A total of 1427 unique patients accounted for 1575 admissions. In 147 admissions, RAI was ≥8. RAI <8 had negative predictive value (NPV) of 0.98 (95% CI 0.97-0.99); RAI ≥ 8 had positive predictive value (PPV) of 0.37 (95% CI 0.30-0.46) to predict days 2 to 4 sAKI (area under the receiver operating characteristic curve [AUC-ROC] 0.88 [95% CI 0.84-0.92]). Of 147 RAI+ patients, 89 had NGAL available. RAI/NGAL combination improved PPV (0.64, 95% CI 0.50-0.79) without decrement in NPV (0.98, 95% CI 0.97-0.98). Conclusion: AKI biomarker assessment directed by risk stratification improves prediction of sAKI in critically ill children and young adults. This CDS process has potential to enrich the population for interventional study, although improvement to adherence to CDS is needed.

Use of the Selective Cytopheretic Device in Critically Ill Children.

INTRODUCTION: Critically ill children with acute kidney injury (AKI) requiring continuous kidney replacement therapy (CKRT) are at increased risk of death. The selective cytopheretic device (SCD) promotes an immunomodulatory effect when circuit ionized calcium (iCa2+) is maintained at <0.40 mmol/l with regional citrate anticoagulation (RCA). In a randomized trial of adult patients on CRRT, those treated with the SCD maintaining an iCa2+ <0.40 mmol/l had improved survival/dialysis independence. We conducted a US Food and Drug Administration (FDA)-sponsored study to evaluate safety and feasibility of the SCD in 16 critically ill children. METHODS: Four pediatric intensive care units (ICUs) enrolled children with AKI and multiorgan dysfunction receiving CKRT to receive the SCD integrated post-CKRT membrane. RCA was used to achieve a circuit iCa2+ level <0.40 mmol/l. Subjects received SCD treatment for 7 days or CKRT discontinuation, whichever came first. RESULTS: The FDA target enrollment of 16 subjects completed the study from December 2016 to February 2020. Mean age was 12.3 ± 5.1 years, weight was 53.8 ± 28.9 kg, and median Pediatric Risk of Mortality II was 7 (range 2-19). Circuit iCa2+ levels were maintained at <0.40 mmol/l for 90.2% of the SCD therapy time. Median SCD duration was 6 days. Fifteen subjects survived SCD therapy; 12 survived to ICU discharge. All ICU survivors were dialysis independent at 60 days. No SCD-related adverse events (AEs) were reported. CONCLUSION: Our data demonstrate that SCD therapy is feasible and safe in children who require CKRT. Although we cannot make efficacy claims, the 75% survival rate and 100% renal recovery rate observed suggest a possible favorable benefit-to-risk ratio.

Early Sequential Risk Stratification Assessment to Optimize Fluid Dosing, CRRT Initiation and Discontinuation in Critically Ill Children with Acute Kidney Injury: Taking Focus 2 Process Article.

BACKGROUND: Acute Kidney Injury (AKI) is common in critically ill children and is associated with increased morbidity and mortality. Recognition and management of AKI is often delayed, predisposing patients to risk of clinically significant fluid accumulation (Fluid Overload (FO)). Early recognition and intervention in high risk patients could decrease fluid associated morbidity. We aim to assess an AKI Clinical Decision Algorithm (CDA) using a sequential risk stratification strategy integrating the Renal Angina Index (RAI), urine Neutrophil Gelatinase-Associated Lipocalin (NGAL) and the Furosemide Stress Test (FST) to optimize AKI and FO prediction and management in critically ill children. METHODS/DESIGN: This single center prospective observational cohort study evaluates the AKI CDA in a Pediatric Intensive Care Unit (PICU). Every patient ≥ 3 months old has the risk score RAI calculated automatically at 12 hours of admission. Patients with a RAI ≥ 8 (fulfilling renal angina) have risk further stratified with a urine NGAL and, if positive (NGAL ≥ 150ng/mL), subsequently by their response to a standardized dose of furosemide (namely FST). RAI negative or NGAL negative patients are treated per usual care. FST-responders are managed conservatively, while non-responders receive fluid restrictive strategy and/or continuous renal replacement therapy (CRRT) at 10%-15% of FO. 2100 patients over 3 years will be evaluated to capture 210 patients with severe AKI (KDIGO Stage 2 or 3 AKI), 100 patients with >10% FO, and 50 requiring CRRT. Primary analyses: Standardizing a pediatric FST and assessing prediction accuracy of CDA for severe AKI, FO>10% and CRRT requirement in children. Secondary analyses in patients with AKI: Renal function return to baseline, RRT and mortality within 28 days. DISCUSSION: This will be the first prospective evaluation of feasibility of AKI CDA, integrating individual prediction tools in one cohesive and comprehensive approach, and its prediction of FO>10% and AKI, as well as the first to standardize the FST in the pediatric population. This will increase knowledge on current AKI prediction tools and provide actionable insight for early interventions in critically ill children based on their level of risk.

Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.

Eosinophilic esophagitis (EE) is an emerging disorder with a poorly understood pathogenesis. In order to define disease mechanisms, we took an empirical approach analyzing esophageal tissue by a genome-wide microarray expression analysis. EE patients had a striking transcript signature involving 1% of the human genome that was remarkably conserved across sex, age, and allergic status and was distinct from that associated with non-EE chronic esophagitis. Notably, the gene encoding the eosinophil-specific chemoattractant eotaxin-3 (also known as CCL26) was the most highly induced gene in EE patients compared with its expression level in healthy individuals. Esophageal eotaxin-3 mRNA and protein levels strongly correlated with tissue eosinophilia and mastocytosis. Furthermore, a single-nucleotide polymorphism in the human eotaxin-3 gene was associated with disease susceptibility. Finally, mice deficient in the eotaxin receptor (also known as CCR3) were protected from experimental EE. These results implicate eotaxin-3 as a critical effector molecule for EE and provide insight into disease pathogenesis.

Postnatal growth of the clavicle: birth to 18 years of age.

BACKGROUND: The purpose of our study was to perform a large cross-sectional study aimed at determining the postnatal growth pattern of the clavicle from birth to 18 years of age. METHODS: We analyzed the digital chest radiographs of a convenience sample of 961 individuals between birth and 18 years of age. Malrotated radiographs were excluded. Right and left clavicle lengths were measured in millimeters from the most lateral ossified border to the most medial ossified border of each clavicle. Study patients were divided into 19 subgroups with the first group being labeled as "birth to 11 months of age" followed by 1-year-olds, 2-year olds, etc. Patients were also grouped by sex. There was a minimum of 25 patients in each group. RESULTS: At 18 years of age the mean+/-SD clavicle length for females was 149+/-12 mm and for males it was 161+/-11 mm. Although a statistically significant difference (P=0.049) was noted between the length of right and left clavicles it was not clinically significant (0.036 mm). A steady growth rate was noted for both genders from birth to the age of 12 years (8.4 mm/y). Above the age of 12 years there were significant differences in the growth of the clavicles of girls (2.6 mm/y) versus boys (5.4 mm/y) (P<0.001). Our data suggest that females achieve 80% of their clavicle length by 9 years of age and boys by 12 years of age. CONCLUSION: This cross-sectional study establishes that relatively little clavicle growth (20%) remains for girls beyond age 9 years and for boys beyond 12 years. The length of one clavicle may be properly judged by comparing it with the contralateral clavicle. CLINICAL RELEVANCE: Remodeling of the clavicle shaft fractures is currently believed to be proportional to remaining growth. Our study questions the capacity of the clavicle to re-establish normal length beyond the age thresholds we have identified.

Clinical, pathologic, and molecular characterization of familial eosinophilic esophagitis compared with sporadic cases.

BACKGROUND & AIMS: Eosinophilic esophagitis (EE) occurs in families. METHODS: Record review confirmed patient kinship and provided clinical information. Slide review confirmed the diagnosis (threshold peak number > or = 24 eosinophils/high-power field). RESULTS: Fifty-nine members (41 males, 18 females) of 26 families were 3 months to 47 years of age (mean age, 10.3 y) at diagnosis. The only recorded race was Caucasian. In 4 families a parent of an affected male had EE. The most common complaint at diagnosis was dysphagia (68% of patients). Endoscopy showed esophageal mucosal furrows (93% of patients) and exudates (44%). Fifty-one percent had asthma. Skin prick tests to food and aeroallergens were positive in 76% and 71%, respectively. Familial EE characteristics (clinical, endoscopic, pathologic, and global esophageal transcript expression profile analysis) were similar to sporadic EE, except among patients with mucosal furrows: familial patients had lower peak eosinophil counts in the distal esophagus (P = .03) compared with sporadic patients. The basic characteristics of EE (eg, eosinophil levels, rate of atopy) did not vary with patient age. By using genome-wide microarray analysis, no significant differences (P < .05, false-discovery rate) were observed between familial and sporadic EE. Among all patients, chest pain was more common in females (P = .02), and thickened mucosa was more common in males (P = .006). CONCLUSIONS: These data support a familial pattern of inheritance of EE and a pathogenesis shared with sporadic EE. EE should be considered in symptomatic family members of patients who have EE.

Interplay of adaptive th2 immunity with eotaxin-3/c-C chemokine receptor 3 in eosinophilic esophagitis.

BACKGROUND: Pediatric eosinophilic esophagitis (EE) is a recently described disorder associated with atopy. Although studies of esophageal tissue suggest that Th2 cytokines and eotaxin-3 may be crucial in disease pathogenesis, little is known about the systemic immunological phenotypes of children with EE. OBJECTIVES: To define the phenotypes of peripheral blood eosinophils and lymphocytes in EE and to examine for correlations between these parameters and tissue eosinophil numbers and disease severity. PATIENTS AND METHODS: Blood was collected from children with EE, atopic control children without EE, and nonatopic control children without EE. Flow cytometry was used to measure eosinophil expression of chemokine receptor 3 (CCR3) and interleukin-5 receptor-alpha (IL-5Ralpha), and intracellular lymphocyte expression of IL-4, IL-5, IL-13, interferon-gamma, and tumor necrosis factor-alpha. Eosinophil numbers and eotaxin-3 mRNA levels were quantitated in esophageal biopsy specimens. RESULTS: Compared with nonatopic control children, EE patients with active disease had increased peripheral blood eosinophil percentages, mean channel of fluorescence (MCF) of CCR3 on eosinophils, and percentage of CD4+ T cells expressing IL-5. Notably, these parameters positively correlated with esophageal eosinophil numbers. Eotaxin-3 tissue expression positively correlated with esophageal eosinophil numbers and peripheral blood eosinophil CCR3 MCF. The percentage of peripheral blood eosinophils, eosinophil CCR3 MCF, and CD4+ T cell expression of IL-5 were lower in EE patients in disease remission than in patients with active disease. CONCLUSIONS: Collectively, these studies demonstrate cooperation between systemic CD4+ Th2-cell-mediated immunity and an enhanced eosinophil-CCR3/eotaxin-3 pathway in EE pathogenesis. Furthermore, the imbalanced Th2 immunity and increased CCR3 expression are reversible with disease remission.

Reliable individualized monitoring improves cholesterol control in kidney transplant recipients.

OBJECTIVE: To develop and evaluate a system for reliable and efficient individualized risk-based monitoring of cholesterol and 11 other tests after kidney transplantation in children. METHODS: We identified system components that drive reliable individualized monitoring and used quality improvement methods to develop and implement interventions, including (1) monitoring schedules individualized by dyslipidemia risk assigned to each patient, (2) automated previsit decision support from our electronic medical record, (3) standardized work flow and responsibility, and (4) automated forwarding of results to providers. We measured the proportion of patients due for cholesterol testing who had it performed within 1 week of their clinic visit and the proportion of patients in our population who achieved low-density lipoprotein (LDL) cholesterol control at baseline and for 2 years after improved monitoring. RESULTS: The proportion of visits in which cholesterol monitoring was completed when indicated improved from 80% to 98% within 8 months and was sustained for more than 1 year. The number of patients with controlled LDL (<130 mg/dL, 3.3 mmol/L) improved from 44 (71%) of 62 at the start of our project to 58 (94%) of 62 (P = .002) at an average follow-up of 24 months. CONCLUSIONS: Using quality improvement and health information technology, we achieved sustained, reliable and efficient personalized monitoring of cholesterol and 11 other tests. This approach enabled substantial improvement in LDL cholesterol control. Structured methods of system redesign that leverage information technology systems hold promise for rapidly achieving reliable individualized care in other settings.

Risk of tacrolimus toxicity in CYP3A5 nonexpressors treated with intravenous nicardipine after kidney transplantation.

BACKGROUND: Tacrolimus is commonly prescribed for immunosuppression, yet it can cause acute and chronic kidney injury. Continuous intravenous nicardipine (CIVN), prescribed for posttransplant hypertension, inhibits tacrolimus metabolism by cytochrome P450 (CYP) 3A4 and could lead to tacrolimus overexposure in patients genetically lacking the alternative pathway for tacrolimus metabolism, CYP3A5. METHODS: We compared maximum 12-hr tacrolimus trough levels (MaxC0) and dose-adjusted MaxC0 in 12 cases treated with CIVN immediately after kidney transplantation with 26 controls (no CIVN). CYP3A5 genotype was determined for all cases. RESULTS: Eight cases not expressing CYP3A5 (CYP3A5*3/*3) had higher median MaxC0 (24.3 ng/mL) than four cases expressing CYP3A5 (CYP3A5*1/*1; 13.9 ng/mL, P=0.028) and controls (14.6 ng/mL, P=0.003). Compared with the other two groups combined, CYP3A5*3/*3 cases had higher median dose-adjusted MaxC0 (330 vs. 175, P=0.012), less time to MaxC0 (42 vs. 72 hr, P<0.001), and more scheduled tacrolimus doses held per patient (1.75 vs. 0.4, P=0.007). Six of eight (75%) CYP3A5*3/*3 cases had potentially toxic MaxC0 (>20 ng/mL) compared with none of four CYP3A5*1/*1 cases and 3 of 26 (11.5%) controls (P<0.001, CYP3A5*3/*3 cases vs. all others). CONCLUSION: CYP3A5 nonexpressors simultaneously treated with tacrolimus and CIVN may be at increased risk for tacrolimus toxicity.

Pediatric patients with eosinophilic esophagitis: an 8-year follow-up.

BACKGROUND: Eosinophilic esophagitis (EE) is a gastrointestinal disorder that is increasingly diagnosed in pediatric patients. OBJECTIVE: We aimed to define, in pediatric patients with EE, their demographic and atopic characteristics, the histopathology of all segments of the gastrointestinal tract, and the effect of therapeutic interventions on the natural history. METHODS: We conducted a retrospective analysis of a database of pediatric patients with EE followed over a period of 8 years. RESULTS: In 89 pediatric patients with EE, male sex (78.6%), white race (94.4%), young age at diagnosis, mean +/- SD, 6.2 +/- 4.8 years, and atopy with sensitization to environmental and food allergens in 79% and 75%, respectively, were prevalent. Patients had EE of the proximal and distal esophagus, and 77% had in addition either mucosal eosinophilia or noneosinophilic histopathology in the stomach, duodenum, and colon. EE was chronic, with a duration of mean +/- SD, 0.91 +/- 0.84 years, until first resolution, and was recurrent; of 66% of the patients who had resolution, 79% later relapsed. CONCLUSION: Eosinophilic esophagitis in the pediatric population is a chronic and relapsing condition, associated with atopy and sometimes with subsequent histopathology in segments of the gastrointestinal tract other than the esophagus. CLINICAL IMPLICATIONS: Physicians evaluating pediatric patients with chronic gastrointestinal symptoms should consider the diagnosis of EE, particularly in young white male patients with atopy. Once diagnosed and treated, the physicians should follow the patients over a period of several years because the course of the disease is protracted, other gastrointestinal segments may be affected, and relapses are common.

Potential of blood eosinophils, eosinophil-derived neurotoxin, and eotaxin-3 as biomarkers of eosinophilic esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EE) is an increasingly recognized disorder characterized by eosinophilic inflammation of the esophageal mucosa, and typically requires serial invasive endoscopic biopsy examinations to document the characteristic histologic features of the disorder. The aim of this study was to identify noninvasive biomarkers that correlated with disease activity and response to treatment as measured by esophageal eosinophilia. METHODS: A prospective, cross-sectional analysis was performed on 47 pediatric patients undergoing endoscopic evaluation of possible EE. Blood samples were collected for measurement of peripheral blood absolute eosinophil count (AEC) and levels of eosinophil-derived neurotoxin (EDN), eotaxin-1, -2, and -3, and interleukin-5. Stool samples were collected for measurement of EDN. Biomarker levels were correlated with esophageal eosinophil density, and differences in biomarker levels based on disease activity and treatment were determined. RESULTS: AEC, plasma EDN levels, and eotaxin-3 levels significantly correlated with esophageal eosinophil density (AEC: r = 0.56, P < .0001; EDN: r = 0.54, P < .0001; eotaxin-3: r = 0.32, P = .04), and were increased in patients with active EE vs controls (AEC: 440 vs 140 eosinophils/muL, P < .05; EDN: 50.3 vs 31.1 ng/mL, P = .01; eotaxin-3: 37.7 vs 11.5 pg/mL, P = .01). Cut-off values were established to maximize the sensitivity, specificity, and predictive values of these biomarkers alone and in combination. Eotaxin-1, eotaxin-2, interleukin-5, and fecal EDN levels did not correlate with esophageal eosinophil density, and were not increased in active EE vs controls or those with inactive EE. CONCLUSIONS: These data show that blood levels of AEC, EDN, and eotaxin-3 may have value as noninvasive biomarkers for monitoring EE.

A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis is an increasingly recognized disorder with distinctive endoscopic, histologic, and allergic features. Although several therapies are advocated, no placebo-controlled trials have been conducted. We aimed to determine the efficacy of swallowed fluticasone propionate (FP) in the treatment of eosinophilic esophagitis. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of swallowed FP in pediatric patients with active eosinophilic esophagitis. Thirty-six patients were randomly assigned to receive either 880 mug of FP (21 patients) or placebo (15 patients) divided twice daily for 3 months. The primary end point was histologic remission, defined by a peak eosinophil count of